S-triazines for treating gastrointestinal hyperacidity and ulceration

ABSTRACT

THE 2-AMINO-4-ANILINO-6-STUBSTITUTED 1,3,5-TRIAZINE COMPOUNDS OF THIS INVENTION ARE USEFUL IN THE TREATMENT OF GASTROINTESTINAL HYPERACIDITY AND ULCERATION. THESE COMPOUNDS ALSO HAVE UTILITY AS ANTIHYPERTENSIVE AGENTS.

United States Patent 3,810,985 S-TRIAZINES FOR TREATING GASTROINTES-TINAL HYPERACIDITY AND ULCERATION Julius Diamond, Lafayette Hill, Pa.,assignor to William H. Rorer, Inc., Fort Washington, Pa.

No Drawing. Original application Oct. 14, 1971, Ser. No. 189,405, nowPatent No. 3,758,469. Divided and this application Mar. 1, 1973, Ser.No. 337,031

Int. Cl. A61k 27/00 US. Cl. 424-249 3 Claims ABSTRACT OF THE DISCLOSUREThe 2-amino-4-anilino-6-substituted 1,3,5-triazine compounds of thisinvention are useful in the treatment of gastrointestinal hyperacidityand ulceration. These compounds also have utility as antihypertensiveagents.

CROSS REFERENCE TO RELATED APPLICATIONS This is a divisional applicationof Serial No. 189,405, filed October 14, 1971, now Patent No. 3,758,469.

SUMMARY OF THE INVENTION This invention describes novel2-amino-4-anilino-6- substituted 1,3,5-triazines, processes forpreparing the same and their method of treatment as medicinal agents.The disclosed 2 amino-4-anilino-6-substituted-l,3,5-triazines of thisinvention are useful in treating gastrointestinal hyperacidity andulceration. Further, these triazines have utility as antihypertensiveagents. When the compounds of this invention are administered to mammalsthey afford significant relief for gastrointestinal hyperacidity andulceration and for hypertension disorders.

BACKGROUND OF THE INVENTION The pharmaceutical compositions which havebeen used as antisecretory and spasmolytic agents have been such asatropine, homatropine, propantheline bromide, dicyclomine hydrochlorideand other compounds which are structurally dissimilar to the triazinesof this invention. Due to the anti-cholinergic properties of these knowncompounds, they produce undesirable side effects such as mydriasis,Xerotomia, cyclopegia and other unwanted effects.

I have unexpectedly found that 2-amino-4-anilino-6-substituted-1,3,5-triazine compounds have valuable pharmacologicalproperties.

I have found 2-amino-4-anilino-fi-substituted-1,3,5- triazines whichpossess useful gastric, anti-secretory and spasmolytic andantiulcerogenic properties.

I have further found that the2-amino-4-anilino-6-substituted-l,3,5compounds of this invention aresubstantially void of the anticholinergic side effects which accompanyheretofor 'known gastric antisecretory and spasmolytic agents.

I have found a simple and effective method for treating gastrichyperacidity and gastrointestinal ulceration such as duodenal and pepticulceration.

I have found that the Z-amino-4-anilino-6-substituted- 1,3,5-triazinesof this invention possess useful antihypertensive properties.

i I have again found that these2-amino-4-anilino-6-substituted-1,3,5-triazine compounds are novel andconveniently synthetized.

DESCRIPTION AND PREFERRED EMBODIMENT This invention comprises a class ofnovel chemical compounds which contain an anilino radical which isattached to the 4 position of a 2-amino-6-substituted- 1,3,5-triazinering.

3,810,985 Patented May 14, 1974 This invention also described a newmethod of treating gastrointestinal disorders and diseases andgastrointestinal therapeutical compositions which comprises theadministration of a compound having the structural formula as shown inFIG. I.

where R R R R and R may be the: same or different and are hydrogen,halo, loweralkyl, nitro, amino, acylamino,

mono-and diloweralkylamino, cyano, haloloweralkyl,

and their nontoxic addition salts.

The more preferred compounds for a method of treating gastrointestinaldisorders and diseases and for use in gastrointestinal therapeuticcompositions embrace those compounds of structural Formula I where:

R R R R and R may be the same or dilferent and are hydrogen, halo,haloloweralkyl or nitro;

R is loweralkyl, loweralkenyl or haloloweralkyl; and

R is hydrogen.

The most preferred compounds for a method of treating gastrointestinaldisorders and diseases and for use in gastrointestinal therapeuticcompositions embrace those compounds of structural Formula I where:

R R R R and R may be the same or different and are hydrogen, chloro,'bromo, fiuoro or trifluoromethyl;

R is methyl, ethyl, propyl, i-prop-yl, butyl, i-butyl, secbutyl,t-butyl, pentyl, hexyl, allyll, methallyl, propargyl, monohalomethyl,dihalomethyl, trihalomethyl, haloethyl or halopropyl; and

R is hydrogen.

In the descriptive portions of this invention, the following definitionsapply:

The term lower alkyl refers to an alkyl hydrocarbon group containingfrom 1 to about 8 carbon atoms which may be straight chained orbranched.

The term acy radical may be any organic radical derivative from anorganic acid by its removal of the hydroxyl group such as acetyl,propionyl, benzoyl, etc. A lower acyl radical would contain up to about8 carbon atoms.

The loweralkoxy radical signifies an alkoxy group containing from 1 toabout 6 carbon atoms which may be straight chained or branched.

The term loweralkenyl refers to an alkenyl hydrocarbon group containingfrom 2 to about 8 carbon atoms which may be straight chained orbranched.

The loweralkynyl radicals refer to an alkynyl hydrocarbon groupcontaining from 2 to about 8 carbon atoms which may be straight chainedor branched.

This invention also describes novel chemical compounds which aregenerically described by the structural formula as shown in FIG. II:

where The more preferred compounds of Formula II are described where Xis hydrogen, fiuoro, chloro, or bromo;

Y is hydrogen, fiuoro, chloro, bromo, nitro, or haloloweralkyl;

Z is haloloweralkyl, fluoro, bromo (provided at least one of X, Y and Ris other than hydrogen) or chloro (provided X or R' is other thanhydrogen and when Z is 3-chloro then X is other than 4-chloro when Y andR' are hydrogen;

R is loweralkyl, loweralkenyl or haloloweralkyl; and

R is hydrogen.

The most preferred compounds of Formula II are described where X ishydrogen, chloro or bromo;

Y is hydrogen, fluoro, chloro or bromo;

Z is trifluoromethyl, fluoro, bromo (provided at least one of X, Y and Ris other than hydrogen) or chloro (provided X or R is other thanhydrogen and when Z is 3-chloro then X is other than 4-chloro when Y andR are hydrogen;

R is methyl, ethyl, propyl, i-propyl, butyl, i-butyl, secbutyl, t-butyl,pentyl, hexyl, allyl, methallyl, propargyl, monohalomethyl,dihalomethyl, trihalomethyl, haloethyl or halopropyl; and

R is hydrogen.

It is well known in the pharmacological arts that nontoxic acid additionsalts of pharmacologically active amine compounds do not ditfer inactivities from their free base. The salts merely provide a convenientsolubility factor. The amines of this invention may be readily convertedto their nontoxic acid addition salts by customary methods in the art.The nontoxic salts of this invention are those salts the acid componentof which is pharmacologically acceptable in the intended dosages; suchsalts would include those prepared from inorganic acids, organic acids,

higher fatty acids, high molecular weight acids, etc., and include suchas:

hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methane sulfonic acid, benzene sulfonic acid, aceticacid, propionic acid, malic acid, succinic acid, glycolic acid, lacticacid, salicylic acid, benzoic, acid, nicotinic acid, phthalic acid,stearic acid, oleic acid, abietic acid, etc.

Representative compounds of this invention which are particularly usefulare as follows:

2-amino-6-ethyl-4-anilino-1,3,5-triazine 2amino-6-ethyl-4-(o-chloroanilino 1,3,5 -triazine 2-amino-6-ethyl-4- (m-chloroanilino l,3 ,S-triazine 2-amino-6-ethyl-4- (p-chloroanilino -1,3,5-triazine2-amino-6-ethyl-4-(2,3-dichloroanilino) -1,3,5-triazine2-amino-6-ethyl-4- (2,4-dichloroanilino)-1,3,5-triazine2-amino-6-ethyl-4- 2,5 -dichloroanilino -1,3,5 -triazine2-amino-6-ethyl-4-(2,6-dichloroanilino)-1,3,5-triazine2-amino-6-ethy1-4- 3,4-dichloroanilino 1,3,5 -triazine2-amino-6-ethyl-4- (3,5-dichloroanilino) -1,3,5-triazine2-amino-6-ethyl-4-(2,3,4-trichl0roanilino) -1,3,5-triazine2-amino-6-ethyl-4- 2,3 ,5 -trichloroanilino 1 ,3 ,5 -triazine2-amino-6-ethyl-4- (2,3 ,6-trich1oroanilino)-1,3 ,5 -triazine2-amino-6-ethyl-4-(2,4,5-trichloroanilino)-1,3,5-triazine2-amino-6-ethy1-4-(2,4,6-trichloroanilino)-1 ,3 ,5 -triazine2-amino-6-ethyl-4- 3 ,4,5-trichloroanilino)-1,3,5-triazine2-amino-6-ethyl-4- (p-bromoanilino) -1,3,5-triazine 2-amino-6-ethyl-4-(o-fluoroanilino)-1,3,5-triazine2-amino-6-ethyl-4-(m-fiuoroanilino)-1,3,5-triazine 2-amino-6-ethyl-4-(pfluoroanilino)-1,3,5-triazine 2-amino-6-ethyl-4- (p-iodoanilino-1,3,5-triazine 2-amino-6-ethyl-4-(p-methylanilino) -1,3,5-triazine2-amino-6-ethyl-4-(p-nitroani1ino)-1,3,5-triazine2-amino-6-ethyl-4-(p-arninoanilino)-1,3,5-triazine 2-amino-6-ethyl-4-p-acetylaminoanilino) 1,3,5 -triazine 2-amino-6-ethyl-4-(p-methylaminoanilino)-1,3 ,5 -triazine2-amino-6-ethyl-4-(p-dimethylaminoanilino) -1,3 ,5

triazine 2-amino-6-ethyl-4-(p-cyanoanilino)-1,3 ,5 -triazine2-arnino-6-ethyl-4- (o-trifluoromethylanilino) -1,3,5-

triazine 2-amino-6-ethyl-4-(m-trifluoromethylanilino)-1,3,5-

triazine 2-amino-6-methyl-4- (p-trifluoromethylanilino) l ,3,5-

triazine 2-amino-6-ethyl-4-(p-trifiuoromethoxyanilino)-1,3,5-

triazine 2-amino-6-ethyl-4-(p-methoxyanilino)-1,3,5-triazine2-amino-6-ethyl-4- (p-hydroxyanilino 1,3 ,5 -triazine2-amino-6-ethyl-4-(p-carboxyanilino )-1,3,5-triazine2-amino-6-ethyl-4-(p-carbethoxyanilino)-1,3,5-triazine2-amino-6-ethyl-4- (p-sulfonamidoanilino l ,3,5-triazine2-amino-6-ethyl-4- (p-dimethylsulfonamidoanilino 1,3,5 -triazine2-amino-6-ethyl-4- (p-trifiuoroacetylanilino)-1,3,5-

triazine 2-amino-6-ethyl-4- (p-trifiuoromethylsulfonylanilino 1,3,S-triazine 2-amino-6-ethyl-4- (p-di-trifluoromethylsulfonamidoanilino1,3,5 -triazine 2-amino-6-ethyl-4-(p-phenoxyanilino)-1,3,5-triazine2-amino-6-ethyl-4- (p- [p'-chlorophenoxy] anilino) 1,3 ,S-triazine2-amino-6-ethyl-4- (p-acetoxyanilino)-1,3,5-triazine 2-amino-6-ethyl-4-(p-biphenylylanilino) -1,3 ,5 -triazine 2-amino-6-ethyl-4- (p- [4'-chlorobiphenylyl] anilino 1,3,5-triazine2-arnino-6-ethyl-4-(p-acetylanilino) -1,3,5-triazine 2-am-ino-6-ethyl-4-(p-mercaptoanilino)-1,3,5-triazine2-amino-6-ethy1-4-(p-methylthioanilino)-1,3,5-triazine2-amino-6-ethyl-4- (p-methylsulfinylanilino)-1,3,5-

triazine 2-a-mino-6-ethyl-4- (p-methylsulfonylanilino)-1,3,5-

triazine Condensation of a l-substituted phenylbiguanide with an acidhalide or acid anhydride in the presence of an inert solvent results inring closure to the corresponding 2-acylamino-6-R-4-anilino-1,3,5-triazine.

When the above acylating agent is replaced with an acid ester or amidethen the product prepared is a 2- amino-6-R-4-anilino-1,3,5-triazine.

RCOOR" OK i RCONR N NH-- z HNH where R" is loweralkyl.

The condensation reaction is normally carried out in the presence of aninert solvent and it is preferable to use a polar solvent such asmethanol, ethanol, 2-ethoxyethanol, dimethylformamide, acetic acid etc.The reaction may also be carried out using an excess of the reactant assolvent. Reaction is preferably carried out using increased temperature.The biguanide may be present in the form of a salt. Isolation of thetriazine product is by any method known in the art such as evaporatingthe reaction mixture to dryness, adding cold aqueous base and extractingor filtering the triazine product.

The biguanide compounds used as starting materials in this invention areeither known compounds or they may be prepared by reaction of acyanoguanide and an aniline in the presence of an equimolar amount of amineral acid.

The polar medium may be aqueous, partially aqueous or non-aqueous andsolvents such as dimethylsulfoxide, diethyleneglycol, tetrahydrofuran,dimethylformamide, etc. The reaction is usually carried out at raisedtemperatures and isolation is by any method known in the art.

Appropriately desired X, Y and Z substituents can be prepared at variousstages of synthesis using suitable reaction in order to convert onegroup to another. Thus, for example, nitration of the anilide can becarried out to obtain ortho and/or para substitution with or withoutsubstituents present. This may then be reduced to an amine group whichin turn may be diazotized followed by a Sandmeyer type reaction to yieldchloro or bromo. The diazo compound may be converted to a cyano withcuprous cyanide; iodo with potassium iodide, a hydroxy or alkoxy withwater or alcohol. The diazonium fluoroborate may also be formed and thenthermally decomposed to the fluoro compound. The amine may also bemonoor dialkylated or acetylated. Halogenation may be carried out on theaniline to obtain ortho and/or para chloro, bromo or iodo substituents.The chloro, bromo or iodo compound may then be treated with cuprouscyanide to obtain the cyano compound. The chloro or bromo compound maybe reacted with trifluoromethyliodide and copper powder at about 150 C.to obtain the trifluoromethyl. Reaction of the chloro or bromo withmethanesulfinate in quinoline at about 150 C. results in themethylsulfonyl.

When substitution is desired in the meta position, nitration orhalogenation may be carried out on an acetophenone. The resulted metasubstituted compound may then be converted to the oxime and treatedunder Beckmann rearrangement conditions to the acetanilide.

In an analogous manner other reactions known in the art may also beemployed and further methods are described in the examples.

I have found that the compounds of this invention have an effectivedegree of gastric anti-secretory activity and effectively reduce thevolume and the acidity of the gas tric fluid in humans and mamals. Stillfurther, these compounds produce a considerable spasmolytic action onthe gastrointestinal musculature, i.e., they reduce the peristalticaction of the gastrointestinal musculature which is manifiested by adelay in gastric emptying time.

Until now, the known antiulcerogenic compounds which showed gastricantisecretory and gastrointestinal spasmolytic action have included suchagents as atropine, homatropine, propantheline, dicylomine, etc. Thesecompounds, however, cause accompanying undesirable anticholinergicproperties such as mydriasis, xerostomia, cyclopegia, etc. I have foundthat the 2-amino-4-anilino 6-substitued-l,3,5-triazines of thisinvention are particularly useful as anti-secretory, anti-spasmodic andanti-ulcerogenic agents because they are essentially devoid of theseunwanted effects.

In particular the triazines as herein described are useful in thetreatment of such ulcerogenic disorders and diseases as duodenal ulcerand peptic ulcer.

I have also found that the 2-amino-4-anilino-G-substituted1,3,5-triazine compounds of this invention are therapeutically usefulfor their anti-hypertensive properties. They provide sgnificantreduction in hyeptensive conditions and disorders and afford relief toassociated organs affected by the hypertensive disease.

For all these purposes, the2-amino-4-anilino-6-substituted-1,3,5-triazines of this invention can benormally administered orally or parenterally. Orally they may beadministered as tablets, aqueous or oily suspension, dispersible powdersor granules, emulsions, hard or soft capsules, or syrups or elixirs. Theterm parenteral as used herein, includes subcutaneous injection,intravenous, intramuscular or intrasternal injection or infusiontechniques.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositons and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation.

Further, these compounds may be tabletedor otherwise formulated so thatfor every 100 parts by weight of the composition, there are presentbetween 5 and parts by weight of the active ingredient. The dosage unitform will generally contain between about 1 mg. and about 500 mg. of theactive ingredients of this invention. The preferred unit dose is betweenabout 10 mg. and about mg.

The dosage regiment in carrying out the methods of this invention isthat which insures maximum thereapeutic response until improvement isobtained and thereafter the minimum etfective level which gives relief.Thus, in general, the dosages are those that are therapeuticallyefiective in the treatment of ulcerogenic and hypertension diseaseconditions or symptoms. In general, the daily dose can be between about0.1 mg./kg. and 70 mg./kg. (preferably in the range of 1-25 mg./kg/day,bearing in mind, of course, that in selecting the appropriate dosage inany specific case, consideration must be given to the patients weight,general health, age and other factors which may influence response tothe drug.

Various tests in animals have been carried out to show the ability ofthe compounds of this invention to exhibit reactions that can becorrelated with anti-ulcerogenic activity in humans. These tests involvesuch as the effect of the2-amino-4-anilino-6-substituted-1,3,5-triazines on gastric secretion,gastro-intestinal spasm and their mucogenic effect. It has been foundthat the compounds of this invention when tested in the above variety ofsituations show a marked activity.

One such test is the gastric secretion test. This test is carried out asfollows: Shay rats are fasted for 4-8 hours, and water is given ad lib.The rats are selected at random and separated into groups of 10. Theanimals are treated intraduodenally (I.D.) with the test compound or thevehicle immediately subsequent to the ligation of the stomach at thepyloric sphincter. The animals are sacrificed with chloroform at 4 hourspost-drug administration, the stomach is removed and its contents areassayed for volume, pH and total acids.

A second gastric secretion test is carried out on dogs. This is outlinedin the Handbook of Physiology, section 6: Alimentary Canal, volume II:Secretion, American Physiology Society, Washington, D.C., 1967.

It has been found that the compounds of this invention when subjected tothe above gastric secretion tests display a marked ability to decreasegastric volume and gastric acidity. These tests are known to correlatewell with gastric activity in humans and is a standard test used todetermine antisecretory properties.

To determine the anti-ulcer efiectiveness the following test isemployed: Male Wistar rats (130450 grams) are fasted for 24 hours, thengiven reserpine at mg./kg. i.p. Twenty-four hours later, the stomachsare removed and examined for ulceration. Ulcers are graded on 0-4 scaleand the number of ulcers is recorded. Pretreatment with the triazinecompounds of this invention produces a decrease in ulcer grade and thenumber of ulcers compared to the control reserpine-treated rats.

Determination of antispasmodic properties can be carried out by theprocedure as outlined by D. A. Brodie and S. K. Kundrats in theirarticle entitled Effect of Drugs on Gastric Emptying in Rats, Fred.Proc. 24:714 (1955).

The bigunanides of this invention have also been found to be mucogenicagents, that is, they increase the biosynthesis of mucopolysaccharidesof the gastric mucous membrane which is a mechanism for inhibitinggastrointestinal ulcer. This property is determined by the test outlinedin the J. Pharm. Pharmac., 1970, 22, 1434.

Mydriasis is detected by the procedure R. A. Turner, Screening Methodsin Pharmacology, Academic Press, New York, and London, pp. 1745, 1965.Acute toxicity is calculated according to the standardLitchfield-Wilcoxon procedure.

In view of the results of these tests, the pharmacological data clearlyindicates that the 2-amino-4-anilino-6-substituted-1,3,5-triazines ofthis invention can be considered to be effective anti-ulcerogenic agentshaving active gastric antisecretory and antispasmodic properties whichare substantially free of anti-cholinergic side effects and having a lowtoxicity.

Tests in animals may also be carried out to show the ability of the2-amino-6-substituted-1,3,5-triazine compound of this invention toinhibit reactions that can be correlated with hypertensive efiects inhumans. One such test is outlined by Jacques de Champlain, Lawrence R.Krahoff and Julius Axelrod in Circulation Research XXIII: 479(1968).This testing method is known to correlate well with hypertensiveactivity in humans and is a standard tests used to determine.antihypertensive properties. In view of the results of this test, the2-amino-4- anilino-6-substituted-1,3,5-triazine compounds of thisinvention can be considered to be active anti-hypertensive agents.

The following are detailed examples which show the preparation of thecompounds of this invention. They are to be construed as illustrationsof said compounds and not as limitations thereof.

EXAMPLE 1.

2-arnino-6-ethyl-4- (p-trifiuoromethylanilino)- 1,3,5-triazine A mixtureof 5.1 g. (0.028 mole) of l-(p-trifiuoromethylphenyl)biguanide dissolvedin 10 m1. of n-propanol and 4.1 ml. (0.0416 mole) of ethylpropionate isrefluxed on a steam bath for 15 hours. The reaction mixture is thenchilled and evaporated to dryness. The residue is recrystallized fromdichloromethane/heptane mixture. This product is then dissolved in etherand extracted with 2Xl00 ml. of 25% acetic acid followed by 25 ml. of10% sodium hydroxide solution and dried over sodium carbonate.Evaporation to dryness: and recrystallization from isopropanol yields2-amino-6-ethyl-4-(p-trifluoromethylanilino)-1,3,5'-triazine.

When the above procedure is followed, however, the ethylpropionate isreplaced by the reactants of Table I below, then the products of TableII below are prepared.

TABLE I Ethylacetate Ethylbutyrate Ethylpentanoate EthylS-methylbutanoate Ethyl hexanoate Ethyl B-butenoate Ethyl S-butynoateEthyl cyclobutanecarboxylate Ethyl cyclopropylacetate Ethylchloroacetate Ethyl trichloroacetate Ethyl fiuorodichloroacetateEthylpropionate Ethyl isobutyrate Ethyl Z-methylbutanoate Ethyl2,2dimethylpropionate Ethyl heptanoate Ethyl Z-methyl-B-butenoate Ethylcyclopropanecarboxylate Ethyl cyclopentanecarboxylate Ethylcyclohexylacetate Ethyl dichloroacetate Ethyl dibromoacetate Ethyldifluoroacetate Ethyl tritluoroacetate Ethyl 2-chloropropionate Ethylmethoxyacetate Ethyl 2-methoxypropionate Ethyl 2-bromopropionate Ethylpentafluoropropionate Ethyl 3-methoxypropionate Ethyl3-ethoxypropionate.

TABLE II 2-amino-6-methyl-4- (p-trifiuoromethylanilino)-1,3,5-

triazine 2-amino-6-ethyl-4-(p-tri1luoromethylanilino)-1,3,5-

triazine 2-amino-6-ethyl-4- (2,6-dichloro-4-fiuoroanilino) 1,3,5-triazine 2-amino-6-ethyl-4- (2,6-dichloro-4-iodoanilino)-1,3,5-triazine 2-amino-6-ethyl-4- 2,6-dichloro-4-nitroanilino 1,3 ,5-triazine 2-amino-6-ethyl-4- (2,6-dichloro-4-trifiuoromethylanilino)1,3,5 -triazine 2-amino-6-ethyl-4- (2,4-dichloro-6-bromoanilino) 1,3 ,5-triazine 2-amino-6-ethyl-4- (Z-trifiuoromethyl-4-aminoanilino1,3,5-triazine 2-amino-6-ethyl-4-2-trifluoromethyl-4-acetylaminoanilino)-1,3,5-triazine2-amino-6-ethyl-4- (4-amino-3-trifluoromethylanilino) 1,3 ,S-triazine2-amino-6-ethyl-4-(4-dimethylamino-3-trifiuoromethylanilino)-1,3,5-triazine2-amino-6-ethyl-4- 3,S-ditrifluoromethylanilino) 1,3,5-triazine2-amino-6-ethyl-4- (4-hydroxy-3-trifluoromethylanilino 1,3,5-triazine2-amino-6-ethyl-4-(2,4-dinitroanilino) -1,3,5-triazine2-amino-6-ethyl-4- (4-methoxy-3 -trifiuoromethylanilino 1,3,5-triazine2-amino-6-ethy1-4- 3-trifiuoromethyl-4-methoxyanilino 1,3,5-triazine.

EXAMPLE 3 When the condensation of Example 1 is followed and the acidester is selected from Table I, Example 1 and the biguanide startingmaterial is selected from Example 2, then the corresponding product isprepared.

EXAMPLE 4 When the procedure of Example 1 is followed and the reactantsof Table I below are used in place of ethylacetate, then thecorresponding product of Table II below is prepared.

TABLE I Acetic acid chloride N,N-diethylacetamide Propionic anhydrideButyric anhydride Cyclopropionic anhydride Phenylacetic anhydrideCyclopropylacetic acid chloride Allylacetic acid chlorideTrifiuoroacetic anhydride Methoxyacetic acid bromide.

TABLE II 2-acety1amino-6-methyl-4-(p-trifiuoromethylanilino)1,3,5-triazine 2-propionamido-6-propyl-4- (p-trifiuoromethylanilino 1,3,S-triazine 2-butyramido-6-butyl-4-(p-trifiuoromethylanilino)-1,3,5-triazine2-cyclopropionamido-6-cyclopropyl-4-(p-trifiuoromethylanilino)-1,3,5-triazine 2-phenylacetylamino-6-benzyl-4-(ptrifiuoromethylanilino)-1,3 ,S-triazine2-cyclopropylacetylamino-6-cyclopropylmethyl-4-(ptrifluoromethylanilino) -1,3,5-triazine 2-allylacetylamino-6-(4-pentenyl) -4- (p-trifiuoromethylanilino )-1,3,5-triazine2-trifiuoroacetylamino-6-trifluoromethyl-4- (p-trifluoromethylanilino-1,3,5-triazine 2-methoxyacetylamino-6-ethoxy-4-(p-trifiuoromethylanilino) -1,3,5-triazine.

EXAMPLE 5 When the procedure of Example 1 is followed using thereactants of Table I, Example 4 and the biguanide starting materials ofExample 2, then the corresponding product is obtained.

I claim:

1. A method for the treatment of gastrointestinal hyperacidity andulceration in a human or mammal which comprises the oral or parenteraladministration thereto of a therapeutically effective amount of acompound of the formula:

Ra R:

where:

R R R R and R may be the same or difierent and are hydrogen, halo,loweralkyl, nitro, haloloweralkyl, phenyl or halophenyl;

R is loweralkyl, loweralkenyl, loweralkynyl, cycloloweralkyl,cycloloweralkenyl, cycloloweralkylloweralkyl,

cycloloweralkenylloweralkyl, haloloweralkyl, hydroxyloweralkyl orloweralkoxyloweralkyl; and

R is hydrogen or a nontoxic addition salt thereof.

2. The method of claim 1 where:

R R R R and R may be the same or different and are hydrogen, halo,haloloweralkyl or nitro;

R is loweralkyl, loweralkenyl or haloloweralkyl.

3. The method of claim 2 where:

R R R R and R may be the same or different and are hydrogen, chloro,bromo, fluoro or trifiuoromethyl;

R is methyl, ethyl, propyl, i-butyl, sec-butyl, t-butyl,

pentyl, hexyl, allyl, methallyl, propargyl, monohalomethyl,dihalomethyl, trihalomethyl, haloethyl or halopropyl.

References Cited UNITED STATES PATENTS 3,209,003 9/1965 Cutler et al.424-249 X 3,549,760 12/1970 Albert 424-249 ALBERT T. MEYERS, PrimaryExaminer F. E. WADDELL, Assistant Examiner

